Synthesis of fluorescent ionic liquid-functionalized silicon nanoparticles with tunable amphiphilicity and selective determination of Hg2.
Fluorescent silicon nanoparticles have attracted much attention in recent years due to their superior optical properties, strong photostability, low toxicity, and favorable biocompatibility. In this paper, we have prepared imidazolium ionic liquid-functionalized silicon nanoparticles (IL@SiNPs) via a simple one-pot hydrothermal route from 1-(trimethoxysilyl)propyl-3-methylimidazolium chloride that was denoted as [SmIm]Cl and sodium citrate. The synthetic IL@SiNPs could be a novel label-free sensing probe for sensitive and selective detection of Hg2+ ions with energy transfer from IL@SiNPs to Hg2+. A good linear relationship was obtained from 0 to 40 μmol L-1 with a detection limit of 0.45 μM. Furthermore, the solubility of the IL@SiNPs can be facilely converted by anion exchange without complex chemical modification. The ionic liquid-modified SiNPs may show great promise in biological and environmental applications due to their excellent biocompatibility and optical performance.


The electrophysiology of introspection.
To study whether the distinction between introspective and non-introspective states of mind is an empirical reality or merely a conceptual distinction, we measured event-related potentials (ERPs) elicited in introspective and non-introspective instruction conditions while the observers were trying to detect the presence of a masked stimulus. The ERPs indicated measurable differences related to introspection in both preconscious and conscious processes. Our data support the hypothesis that introspective states empirically differ from non-introspective states.


Multimaterial 3D laser microprinting using an integrated microfluidic system.
Three-dimensional (3D) laser micro- and nanoprinting has become a versatile, reliable, and commercially available technology for the preparation of complex 3D architectures for diverse applications. However, the vast majority of structures published so far have been composed of only a single constituent material. Here, we present a system based on a microfluidic chamber integrated into a state-of-the-art laser lithography apparatus. This system is scalable in terms of the number of materials and eliminates the need to go back and forth between the lithography instrument and the chemistry room numerous times, with tedious realignment steps in between. As an application, we present 3D deterministic microstructured security features requiring seven different liquids: a nonfluorescent photoresist as backbone, two photoresists containing different fluorescent quantum dots, two photoresists with different fluorescent dyes, and two developers. Our integrated microfluidic 3D printing system opens the door to truly multimaterial 3D additive manufacturing on the micro- and nanoscale.


Long-term ethanol intoxication reduces inflammatory responses in rats.
The anti-inflammatory effects of long-term ethanol intoxication were determined during ethanol treatment and withdrawal on the basis of neutrophil and eosinophil migration, hind paw edema and mast cell degranulation. Male Wistar rats (180-200 g, around 2 months of age) were exposed to increasing concentrations of ethanol vapor over a 10-day period. One group was evaluated immediately after exposure (treated group - intoxicated), and another was studied 7 h later (withdrawal group). Ethanol inhalation treatment significantly inhibited carrageenan--(62% for the intoxicated group, N = 5, and 35% for the withdrawal group, N = 6) and dextran-induced paw edema (32% for intoxicated rats and 26% for withdrawal rats, N = 5 per group). Ethanol inhalation significantly reduced carrageenan-induced neutrophil migration (95% for intoxicated rats and 41% for withdrawn rats, N = 6 per group) into a subcutaneous 6-day-old air pouch, and Sephadex-induced eosinophil migration to the rat peritoneal cavity (100% for intoxicated rats and 64% for withdrawn rats, N = 6 per group). A significant decrease of mast cell degranulation was also demonstrated (control, 82%; intoxicated, 49%; withdrawn, 51%, N = 6, 6 and 8, respectively). Total leukocyte and neutrophil counts in venous blood increased significantly during the 10 days of ethanol inhalation (leukocytes, 13, 27 and 40%; neutrophils, 42, 238 and 252%, respectively, on days 5, 9 and 10, N = 7, 6 and 6). The cell counts decreased during withdrawal, but were still significantly elevated (leukocytes, 10%; neutrophils, 246%, N = 6). These findings indicate that both the cellular and vascular components of the inflammatory response are compromised by long-term ethanol intoxication and remain reduced during the withdrawal period.


Use of Elderly Allografts in Liver Transplantation.
The use of liver allografts from elderly donors (≥70 years) has increased because of organ shortage and increased life expectancy. The aim of this study is to evaluate the current utilization of elderly donors in United States, recipient selection, and their posttransplant outcomes. A linkage between Scientific Registry of Transplant Recipients and University HealthSystem Consortium databases was performed. Between January 2007 and December 2011, 12,445 liver transplant (LT) recipients were identified and divided into 2 cohorts based on donor age: 70 years or older (n = 540) and younger than 60 years (n = 10,473). Elderly donors accounted for 4.3% of all donors used in the 5-year period. When compared to younger donors, elderly donors were more likely to be women, shared regionally or nationally, and used at higher volume centers. Elderly donor allografts were less likely to be used in recipients with model of end-stage liver disease score higher than 27 (13.2% vs. 23.0%, P < 0.001), hospitalized (16.8% vs. 21.7%, P = 0.03), or on hemodialysis at time of transplant (2.6% vs. 8.2%, P < 0.001). Both recipient groups had similar perioperative mortality, 30-day readmission rates, and short-term patient survival. In the multivariate analysis, including recipient, donor, center and regional factors, donor age 70 years or older was associated with slightly increased risk of graft loss (hazard ratio, 1.3; 95% confidence interval, 1.08-1.56; P = 0.005). The current trend toward the use of elderly donors in liver transplant recipients with low model of end-stage liver disease scores (<27), without hepatitis C, not hospitalized and not on dialysis, is associated with acceptable perioperative outcomes, patient survival, and slightly worse graft survival.


Epidemiology of paediatric chronic fatigue syndrome in Australia.
To estimate the paediatrician-diagnosed incidence of chronic fatigue syndrome (CFS) in Australia, and describe demographic and clinical features, as well as approaches to diagnosis and management. The Australian Paediatric Surveillance Unit facilitates monthly national surveillance of uncommon conditions seen by paediatricians. Data from young people aged <18 years diagnosed with CFS were collected. Incidence was estimated based on new cases reported from April 2015 to April 2016. A total of 164 cases of newly diagnosed CFS in young people aged 4-17 years were identified for inclusion. The estimated national incidence for children aged 4-9 years was 0.25 per 100 000 per annum. In children aged 10-17 years, the estimated incidence of paediatrician-diagnosed cases for Victoria (17.48 per 100 000) was substantially greater than other Australian states (range 1.31-5.51 per 100 000). Most cases were female and Caucasian, most commonly presenting after an infectious illness with symptoms gradual in onset. The majority were diagnosed at least 13 months after symptom onset. Symptoms, associations, investigations and management strategies were highly variable. Current findings suggest that, consistent with other countries, the Australian incidence of CFS in children aged <10 years is very low. In contrast, the national incidence of CFS in older children and adolescents (aged 10-17 years) is more unclear, with marked variability between geographical regions apparent. This may be due to variation in service accessibility and clinician understanding of CFS. Accordingly, national initiatives to improve equity of care for children with CFS may be required.


Multiple rearrangements in mitochondrial genomes of Isopoda and phylogenetic implications.
In this study, we analyse the evolutionary dynamics and phylogenetic implications of gene order rearrangements in five newly sequenced mitochondrial (mt) genomes and four published mt genomes of isopod crustaceans. The sequence coverage is nearly complete for four of the five newly sequenced species, with only the control region and some tRNA genes missing, while in Janira maculosa only two thirds of the genome could be determined. Mitochondrial gene order in isopods seems to be more plastic than that in other crustacean lineages, making all nine known mt gene orders different. Especially the asellote Janira is characterized by many autapomorphies. The following inferred ancestral isopod mt gene order exists slightly modified in modern isopods: nad1, tnrL1, rrnS, control region, trnS1, cob, trnT, nad5, trnF. We consider the inferred gene translocation events leading to gene rearrangements as valuable characters in phylogenetic analyses. In this first study covering major isopod lineages, potential apomorphies were identified, e.g., a shared relative position of trnR in Valvifera. We also report one of the first findings of homoplasy in mitochondrial gene order, namely a shared relative position of trnV in unrelated isopod lineages. In addition to increased taxon sampling secondary structure, modification in tRNAs and GC-skew inversion may be potentially fruitful subjects for future mt genome studies in a phylogenetic context.


Prediction and Interpretable Visualization of Retrosynthetic Reactions Using Graph Convolutional Networks.
Recently, many research groups have been addressing data-driven approaches for (retro)synthetic reaction prediction and retrosynthetic analysis. Although the performances of the data-driven approach have progressed because of recent advances of machine learning and deep learning techniques, problems such as improving capability of reaction prediction and the black-box problem of neural networks persist for practical use by chemists. To spread data-driven approaches to chemists, we focused on two challenges: improvement of retrosynthetic reaction prediction and interpretability of the prediction. In this paper, we propose an interpretable prediction framework using graph convolutional networks (GCN) for retrosynthetic reaction prediction and integrated gradients (IG) for visualization of contributions to the prediction to address these challenges. As a result, from the viewpoint of balanced accuracies, our model showed better performances than the approach using an extended-connectivity fingerprint. Furthermore, IG-based visualization of the GCN prediction successfully highlighted reaction-related atoms.


CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells.
We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.


Field Testing Integrated Interventions for Schistosomiasis Elimination in the People's Republic of China: Outcomes of a Multifactorial Cluster-Randomized Controlled Trial.
Despite significant progress, China faces the challenge of re-emerging schistosomiasis transmission in currently controlled areas due, in part, to the presence of a range of animal reservoirs, notably water buffalo and cattle, which can harbor Schistosoma japonicum infections. Environmental, ecological and social-demographic changes in China, shown to affect the distribution of oncomelanid snails, can also impact future schistosomiasis transmission. In light of their importance in the S. japonicum, lifecycle, vaccination has been proposed as a means to reduce the excretion of egg from cattle and buffalo, thereby interrupting transmission from these reservoir hosts to snails. A DNA-based vaccine (SjCTPI) our team developed showed encouraging efficacy against S. japonicum in Chinese water buffaloes. Here we report the results of a double-blind cluster randomized trial aimed at determining the impact of a combination of the SjCTPI bovine vaccine (given as a prime-boost regimen), human mass chemotherapy and snail control on the transmission of S. japonicum in 12 selected administrative villages around the Dongting Lake in Hunan province. The trial confirmed human praziquantel treatment is an effective intervention at the population level. Further, mollusciciding had an indirect ~50% efficacy in reducing human infection rates. Serology showed that the SjCTPI vaccine produced an effective antibody response in vaccinated bovines, resulting in a negative correlation with bovine egg counts observed at all post-vaccination time points. Despite these encouraging outcomes, the effect of the vaccine in preventing human infection was inconclusive. This was likely due to activities undertaken by the China National Schistosomiasis Control Program, notably the treatment, sacrifice or removal of bovines from trial villages, over which we had no control; as a result, the trial design was compromised, reducing power and contaminating outcome measures. This highlights the difficulties in undertaking field trials of this nature and magnitude, particularly over a long period, and emphasizes the importance of mathematical modeling in predicting the potential impact of control intervention measures. A transmission blocking vaccine targeting bovines for the prevention of S. japonicum with the required protective efficacy would be invaluable in tandem with other preventive intervention measures if the goal of eliminating schistosomiasis from China is to become a reality.


A Systematic Review and Meta-Analysis of the Effect of Acupressure on Relieving the Labor Pain.
Numerous studies have been conducted on the effect of acupressure on labor pain, some of which have reported conflicting results. Thus, the present study was performed to critically review the previous studies related to the effect of acupressure administered during labor for relieving labor pain. In this study, databases of the Cochrane Central Register of the Controlled Trials, PubMed/MEDLINE, Scopus, and Web of Science were searched from their establishment until November 5, 2019. All the Randomized Controlled Trials (RCTs) that had compared the use of acupressure with either placebo or nonintervention for relieving the labor pain were included in the study. Meta-analysis was performed using the Comprehensive Meta-Analysis (CMA) software Version 2. The random-effects model was used for pooling the effect sizes across the included studies. The p value <0.05 was considered as statistically significant. Totally, 5853 primary papers were identified in the search, which were narrowed down to 22 studies. The results of meta-analysis showed that the acupressure decreased the labor pain in the intervention group vs. control (-1.67 [-2.29 to -1.05], z = -5.25, p < 0. 001) (Q-value = 788.98, p < 0.001, I-squared = 96.83). No publication bias was found in the included studies (Egger's regression intercept = -1.02, p = 0.76). Although the findings of this meta-analysis showed that the acupressure significantly reduced the labor pain during the active phase of labor compared to the nonintervention or placebo; considering that the quality of the included studies was generally moderate, rigorous RCTs with better design and higher quality are needed to obtain definitive conclusions.


UBC® Rapid Test for detection of carcinoma in situ for bladder cancer.
UBC® Rapid Test is a test that detects fragments of cytokeratins 8 and 18 in urine. We present results of a multicentre study measuring UBC® Rapid Test in bladder cancer patients and healthy controls with focus on carcinoma in situ (CIS) and high-grade bladder cancer. From our study with N = 452 patients, we made a stratified sub-analysis for carcinoma in situ of the urinary bladder. Clinical urine samples were used from 87 patients with tumours of the urinary bladder (23 carcinoma in situ, 23 non-muscle-invasive low-grade tumours, 21 non-muscle-invasive high-grade tumours and 20 muscle-invasive high-grade tumours) and from 22 healthy controls. The cut-off value was defined at 10.0 µg/L. Urine samples were analysed by the UBC® Rapid Test point-of-care system (concile Omega 100 POC reader). Pathological levels of UBC Rapid Test in urine are higher in patients with bladder cancer in comparison to the control group (p < 0.001). Sensitivity was calculated at 86.9% for carcinoma in situ, 30.4% for non-muscle-invasive low-grade bladder cancer, 71.4% for nonmuscle-invasive high grade bladder cancer and 60% for muscle-invasive high-grade bladder cancer, and specificity was 90.9%. The area under the curve of the quantitative UBC® Rapid Test using the optimal threshold obtained by receiveroperated curve analysis was 0.75. Pathological values of UBC® Rapid Test in urine are higher in patients with high-grade bladder cancer in comparison to low-grade tumours and the healthy control group. UBC® Rapid Test has potential to be more sensitive and specific urinary protein biomarker for accurate detection of high-grade patients and could be added especially in the diagnostics for carcinoma in situ and non-muscle-invasive high-grade tumours of urinary bladder cancer.


The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation.
Dynamic interactions between membrane and cytoskeleton components are crucial for T cell antigen recognition and subsequent cellular activation. We report here that the membrane-microfilament linker ezrin plays an important role in these processes. First, ezrin relocalizes to the contact area between T cells and stimulatory antigen-presenting cells (APCs), accumulating in F-actin-rich membrane protrusions at the periphery of the immunological synapse. Second, T cell receptor (TCR)-mediated intracellular signals are sufficient to induce ezrin relocalization, indicating that this protein is an effector of TCR signaling. Third, overexpression of the membrane binding domain of ezrin perturbs T cell receptor clustering in the T cell-APC contact area and inhibits the activation of nuclear factor for activated T cells (NF-AT).


Confusion and conflict in assessing the physical activity status of middle-aged men.
Physical activity (including exercise) is prescribed for health and there are various recommendations that can be used to gauge physical activity status. The objective of the current study was to determine whether twelve commonly-used physical activity recommendations similarly classified middle-aged men as sufficiently active for general health. We examined the commonality in the classification of physical activity status between twelve variations of physical activity recommendations for general health in ninety men aged 45-64 years. Physical activity was assessed using synchronised accelerometry and heart rate. Using different guidelines but the same raw data, the proportion of men defined as active ranged from to 11% to 98% for individual recommendations (median 73%, IQR 30% to 87%). There was very poor absolute agreement between the recommendations, with an intraclass correlation coefficient (A,1) of 0.24 (95% CI, 0.15 to 0.34). Only 8% of men met all 12 recommendations and would therefore be unanimously classified as active and only one man failed to meet every recommendation and would therefore be unanimously classified as not sufficiently active. The wide variability in physical activity classification was explained by ostensibly subtle differences between the 12 recommendations for thresholds related to activity volume (time or energy), distribution (e.g., number of days of the week), moderate intensity cut-point (e.g., 3 vs. 4 metabolic equivalents or METs), and duration (including bout length). Physical activity status varies enormously depending on the physical activity recommendation that is applied and even ostensibly small differences have a major impact. Approximately nine out of every ten men in the present study could be variably described as either active or not sufficiently active. Either the effective dose or prescription that underlies each physical activity recommendation is different or each recommendation is seeking the same prescriptive outcome but with variable success.


Second-order robust regularization cost function for detecting and reconstructing phase discontinuities.
We propose a robust method for computing discontinuous phase maps from a fringe pattern with carrier frequency. Our algorithm is based on the minimization of an edge-preserving regularized cost function, specifically, on a robust regularized potential that uses a paradigm called the plate with adaptive rest condition, i.e., a second-order edge-preserving potential. Given that the proposed cost function is not convex, our method uses as its initial point an overly smoothed phase computed with a standard fringe analysis method and then reconstructs the phase discontinuities. Although the method is general purpose, it is introduced in the context of interferometric gauge-block calibration. The performance of the algorithm is demonstrated by numerical experiments with both synthetic and real data.


Birth weight, infant growth, and childhood body mass index: Hong Kong's children of 1997 birth cohort.
To investigate the association between birth weight, infant growth rate, and childhood adiposity as a proxy for adult metabolic or cardiovascular risk in a Chinese population with a history of recent and rapid economic development. Prospective study in a population-representative birth cohort. Hong Kong Chinese population. Six thousand seventy-five term births (77.5% successful follow-up). Main Exposures Birth weight and growth rate (change in the weight z score) at ages 0 to 3 and 3 to 12 months. Main Outcome Measure Body mass index (BMI) (calculated as the weight in kilograms divided by the height in meters squared) z score at about age 7 years. Each unit increase in the weight z score at ages 0 to 3 and 3 to 12 months increased the BMI z score by 0.52 and 0.33, respectively. Children in the highest birth weight and growth rate tertiles had the highest BMI z scores. In the lowest birth weight tertile, increases in the weight z score at ages 0 to 3 months had a larger effect on the BMI z score in boys (mean difference, 0.88; 95% confidence interval 0.69-1.07) than in girls (mean difference, 0.52; 95% confidence interval, 0.33-0.71); these differences by birth weight, growth rate at ages 0 to 3 months, and sex were significant (P = .007). Faster prenatal and postnatal growth were associated with higher childhood BMI in a population with a recent history of rapid economic growth and relatively low birth weight, suggesting that maximal growth may not be optimal for metabolic risk. However, there may be a developmental trade-off between metabolic risk and other outcomes.


Inhibitory effects of heat shock protein 90 blockade on proinflammatory human Th1 and Th17 cell subpopulations.
Heat shock protein 90 (Hsp90), a chaperone that regulates activity of many client proteins responsible for cellular growth, differentiation, and apoptosis, has been proposed as an important clinical and preclinical therapeutic target in a number of malignancies and autoimmune diseases, respectively. In this study, we evaluated the effects of pharmacological Hsp90 inhibition on human proinflammatory T cell responses. Using anti-CD3 antibody-stimulated human peripheral blood mononuclear cell cultures, we observed that Hsp90 inhibition by non-toxic concentrations of the geldanamycin derivative 17-DMAG significantly blocked T cell proliferation, reduced IFN-γ and IL-17 expression on CD4+ T lymphocytes, and arrested secretion of proinflammatory IFN-γ, TNF-α, and IL-17, cytokines characteristic of Th1 and Th17 cells, respectively. These effects were associated with inhibition of NF-kB activity, upregulation of Hsp70 protein expression, and disruption of T cell-specific nonreceptor tyrosine kinase Lck activation. Our results further support the potential use of Hsp90 inhibitors in patients with autoimmune diseases where uncontrolled Th1 or Th17 activation frequently occurs.


Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS.
Major depression affects about 25% of the patients who have Alzheimer disease and has serious adverse consequences for patients and caregivers. Results of prior antidepressant treatment studies have produced contradictory findings and have not fully assessed the benefits of depression reduction. To assess the efficacy and safety of sertraline hydrochloride for the treatment of major depression in Alzheimer disease, and to evaluate the effect of depression reduction on activities of daily living, cognition, and nonmood behavioral disturbance. Randomized, placebo-controlled, parallel, 12-week, flexible-dose clinical trial with a 1-week, single-blind placebo phase. The study was conducted between January 1, 1998, and July 19, 2001. University outpatient clinic. Forty-four outpatients who have probable Alzheimer disease and major depressive episodes. Sertraline hydrochloride, mean dosage of 95 mg/d, or identical placebo, randomly assigned. Response rate, Cornell Scale for Depression in Dementia, Hamilton Depression Rating Scale, Mini-Mental State Examination, Psychogeriatric Depression Rating Scale-activities of daily living subscale, and Neuropsychiatric Inventory to quantify patient behavior disturbance and caregiver distress. In the sertraline-treated group 9 patients (38%) were full responders and 11 (46%) were partial responders compared with 3 (20%) and 4 (15%), respectively, in the placebo-treated group (P =.007). The sertraline-treated group had greater improvements in the scores for the Cornell Scale for Depression in Dementia (P =.002) and Hamilton Depression Rating Scale (P =.01), and a statistical trend toward less decline in activities of daily living on the Psychogeriatric Depression Rating Scale-activities of daily living subscale (P =.07). There was no difference between the treatment groups in Mini-Mental State Examination (P =.22) or Neuropsychiatric Inventory (P =.32) ratings over time. When full responders, partial responders, and nonresponders were compared, full responders only, or full and partial responders had significantly better ratings on activities of daily living (P =.04), behavioral disturbance (P =.01), and caregiver distress (P =.006), but not on the Mini-Mental State Examination (P =.76). Safety monitoring indicated few differences in adverse effects between the 2 treatment groups. Sertraline is superior to placebo for the treatment of major depression in Alzheimer disease. Depression reduction is accompanied by lessened behavior disturbance and improved activities of daily living, but not improved cognition.


Pseudomonas aeruginosa Exolysin promotes bacterial growth in lungs, alveolar damage and bacterial dissemination.
Exolysin (ExlA) is a recently-identified pore-forming toxin secreted by a subset of Pseudomonas aeruginosa strains identified worldwide and devoid of Type III secretion system (T3SS), a major virulence factor. Here, we characterized at the ultrastructural level the lesions caused by an ExlA-secreting strain, CLJ1, in mouse infected lungs. CLJ1 induced necrotic lesions in pneumocytes and endothelial cells, resulting in alveolo-vascular barrier breakdown. Ectopic expression of ExlA in an exlA-negative strain induced similar tissue injuries. In addition, ExlA conferred on bacteria the capacity to proliferate in lungs and to disseminate in secondary organs, similar to bacteria possessing a functional T3SS. CLJ1 did not promote a strong neutrophil infiltration in the alveoli, owing to the weak pro-inflammatory cytokine reaction engendered by the strain. However, CLJ1 was rapidly eliminated from the blood in a bacteremia model, suggesting that it can be promptly phagocytosed by immune cells. Together, our study ascribes to ExlA-secreting bacteria the capacity to proliferate in the lung and to damage pulmonary tissues, thereby promoting metastatic infections, in absence of substantial immune response exacerbation.


Complications associated with brachioplasty: a literature review.
Paralleling the growth of bariatric surgery, the demand for post-bariatric body-contouring surgery is increasing. Weight loss is the main cause, although not the only one, that drives patients to arm lift surgery. Several surgical techniques have been proposed over the years. Our aim was to consider the complications and outcomes according to the performed technique, through a wide review of the literature. A search on PubMed/Medline was performed using "brachioplasty", "upper arm lifting", and "techniques" as key words. Embase, Medline (OvidSP), Web of Science, Scopus, PubMed publisher, Cochrane, and Google Scholar were searched as well. As inclusion criteria, we selected the clinical studies describing techniques of brachioplasty. We excluded the papers in which complications related to brachioplasty were not specified. We also excluded literature-review articles. We found 27 studies from 1995 to 2015. Overall, 1065 patients were treated. Different techniques were applied. Complications were observed in 308/1065 patients (28.9%). The most frequent complications were hypertrophic scarring, seroma and hematoma. Surgical revision rate ranged from 0 to 21 percent. Nerve damage occurred in a modest percentage of patients (16/1065, 1.5%). No major complications, such as thromboembolism and sepsis, were observed. Brachioplasty is a safe surgical procedure. All the brachioplasty techniques showed positive outcomes, in term of patients' satisfaction and clinical results. Nevertheless, minor complications occurred in a high percentage of patients, regardless the performed surgical procedure. Patients should be informed about the possible formation of hypertrophic scars and nerve injuries.


First case of postmortem study in a patient vaccinated against SARS-CoV-2.
A previously symptomless 86-year-old man received the first dose of the BNT162b2 mRNA COVID-19 vaccine. He died 4 weeks later from acute renal and respiratory failure. Although he did not present with any COVID-19-specific symptoms, he tested positive for SARS-CoV-2 before he died. Spike protein (S1) antigen-binding showed significant levels for immunoglobulin (Ig) G, while nucleocapsid IgG/IgM was not elicited. Acute bronchopneumonia and tubular failure were assigned as the cause of death at autopsy; however, we did not observe any characteristic morphological features of COVID-19. Postmortem molecular mapping by real-time polymerase chain reaction revealed relevant SARS-CoV-2 cycle threshold values in all organs examined (oropharynx, olfactory mucosa, trachea, lungs, heart, kidney and cerebrum) except for the liver and olfactory bulb. These results might suggest that the first vaccination induces immunogenicity but not sterile immunity.


Uphill running does not exacerbate collagenase-induced pathological changes in the Achilles tendon of rats selectively bred for high-capacity running.
The Achilles tendon is a frequent site for degeneration, and advanced understanding of this pathology requires an animal model that replicates the human condition. The aim of this study was to explore whether intratendinous collagenase injection combined with treadmill running created a pathology in the rat Achilles tendon consistent with human Achilles tendinosis. Collagenase was injected into one Achilles tendon of 88 high-capacity running (HCR) rats, which were randomized into treadmill running and cage control groups. Running animals ran at speeds up to 30 m/min on a treadmill at a 15° incline for up to 1 h/d, 5 d/week for 4 or 10 weeks. Cage control animals maintained cage activity. Collagenase induced molecular, histopathological and mechanical changes within the Achilles tendon at 4 weeks. The mechanical changes persisted at 10 weeks; however, the histopathological and majority of the molecular changes were no longer present at 10 weeks. Treadmill running had minimal effect and did not exacerbate the collagenase-induced changes as there were no statistical interactions between the interventions. These data suggest combined intratendinous collagenase injection and treadmill running does not create pathology within the Achilles tendon of rats selectively bred for HCR that is consistent with human Achilles tendinosis.


Use of machine learning to analyse routinely collected intensive care unit data: a systematic review.
Intensive care units (ICUs) face financial, bed management, and staffing constraints. Detailed data covering all aspects of patients' journeys into and through intensive care are now collected and stored in electronic health records: machine learning has been used to analyse such data in order to provide decision support to clinicians. Systematic review of the applications of machine learning to routinely collected ICU data. Web of Science and MEDLINE databases were searched to identify candidate articles: those on image processing were excluded. The study aim, the type of machine learning used, the size of dataset analysed, whether and how the model was validated, and measures of predictive accuracy were extracted. Of 2450 papers identified, 258 fulfilled eligibility criteria. The most common study aims were predicting complications (77 papers [29.8% of studies]), predicting mortality (70 [27.1%]), improving prognostic models (43 [16.7%]), and classifying sub-populations (29 [11.2%]). Median sample size was 488 (IQR 108-4099): 41 studies analysed data on > 10,000 patients. Analyses focused on 169 (65.5%) papers that used machine learning to predict complications, mortality, length of stay, or improvement of health. Predictions were validated in 161 (95.2%) of these studies: the area under the ROC curve (AUC) was reported by 97 (60.2%) but only 10 (6.2%) validated predictions using independent data. The median AUC was 0.83 in studies of 1000-10,000 patients, rising to 0.94 in studies of > 100,000 patients. The most common machine learning methods were neural networks (72 studies [42.6%]), support vector machines (40 [23.7%]), and classification/decision trees (34 [20.1%]). Since 2015 (125 studies [48.4%]), the most common methods were support vector machines (37 studies [29.6%]) and random forests (29 [23.2%]). The rate of publication of studies using machine learning to analyse routinely collected ICU data is increasing rapidly. The sample sizes used in many published studies are too small to exploit the potential of these methods. Methodological and reporting guidelines are needed, particularly with regard to the choice of method and validation of predictions, to increase confidence in reported findings and aid in translating findings towards routine use in clinical practice.


Adhesion of flat-ended pillars with non-circular contacts.
Fibrillar adhesives composed of fibers with non-circular cross-sections and contacts, including squares and rectangles, offer advantages that include a larger real contact area when arranged in arrays and simplicity in fabrication. However, they typically have a lower adhesion strength compared to circular pillars due to a stress concentration at the corner of the non-circular contact. We investigate the adhesion of composite pillars with circular, square and rectangular cross-sections each consisting of a stiff pillar terminated by a thin compliant layer at the tip. Finite element mechanics modeling is used to assess differences in the stress distribution at the interface for the different geometries and the adhesion strength of different shape pillars is measured in experiments. The composite fibrillar structure results in a favorable stress distribution on the adhered interface that shifts the crack initiation site away from the edge for all of the cross-sectional contact shapes studied. The highest adhesion strength achieved among the square and rectangular composite pillars with various tip layer thicknesses is approximately 65 kPa. This is comparable to the highest strength measured for circular composite pillars and is about 6.5× higher than the adhesion strength of a homogenous square or rectangular pillar. The results suggest that a composite fibrillar adhesive structure with a local stress concentration at a corner can achieve comparable adhesion strength to a fibrillar structure without such local stress concentrations if the magnitude of the corner stress concentrations are sufficiently small such that failure does not initiate near the corners, and the magnitude of the peak interface stress away from the edge and the tip layer thickness are comparable.


SK but not IK channels regulate human detrusor smooth muscle spontaneous and nerve-evoked contractions.
Animal studies suggest that the small (SK) and intermediate (IK) conductance Ca(2+)-activated K(+) channels may contribute to detrusor smooth muscle (DSM) excitability and contractility. However, the ability of SK and IK channels to control DSM spontaneous phasic and nerve-evoked contractions in human DSM remains unclear. We first investigated SK and IK channels molecular expression in native human DSM and further assessed their functional role using isometric DSM tension recordings and SK/IK channel-selective inhibitors. Quantitative PCR experiments revealed that SK3 channel mRNA expression in isolated DSM single cells was ∼12- to 44-fold higher than SK1, SK2, and IK channels. RT-PCR studies at the single-cell level detected mRNA messages for SK3 channels but not SK1, SK2, and IK channels. Western blot and immunohistochemistry analysis further confirmed protein expression for the SK3 channel and lack of detectable protein expression for IK channel in whole DSM tissue. Apamin (1 μM), a selective SK channel inhibitor, significantly increased the spontaneous phasic contraction amplitude, muscle force integral, phasic contraction duration, and muscle tone of human DSM isolated strips. Apamin (1 μM) also increased the amplitude of human DSM electrical field stimulation (EFS)-induced contractions. However, TRAM-34 (1 μM), a selective IK channel inhibitor, had no effect on the spontaneous phasic and EFS-induced DSM contractions suggesting a lack of IK channel functional role in human DSM. In summary, our molecular and functional studies revealed that the SK, particularly the SK3 subtype, but not IK channels are expressed and regulate the spontaneous and nerve-evoked contractions in human DSM.


Clinical user experiences of observation and response charts: focus group findings of using a new format chart incorporating a track and trigger system.
Optimising clinical responses to deteriorating patients is an international indicator of acute healthcare quality. Observation charts incorporating track and trigger systems are an initiative to improve early identification and response to clinical deterioration. A suite of track and trigger 'Observation and Response Charts' were designed in Australia and initially tested in simulated environments. This paper reports initial clinical user experiences and views following implementation of these charts in adult general medical-surgical wards. Across eight trial sites, 44 focus groups were conducted with 218 clinical ward staff, mostly nurses, who received training and had used the charts in routine clinical practice for the preceding 2-6 weeks. Transcripts of audio recordings were analysed for emergent themes using an inductive approach. In this exploration of initial user experiences, key emergent themes were: tensions between vital sign 'ranges versus precision' to support decision making; using a standardised 'generalist chart in a range of specialist practice' areas; issues of 'clinical credibility', 'professional autonomy' and 'influences of doctors' when communicating abnormal signs; and 'permission and autonomy' when escalating care according to the protocol. Across themes, participants presented a range of positive, negative or mixed views. Benefits were identified despite charts not always being used up to their optimal design function. Participants reported tensions between chart objectives and clinical practices, revealing mismatches between design characteristics and human staff experiences. Overall, an initial view of 'increased activity/uncertain benefit' was uncovered. Findings particularly reinforced the significant influences of organisational work-based cultures, disciplinary boundaries and interdisciplinary communication on implementation of this new practice chart. Optimal use of all chart design characteristics will be possible when these broader cultural issues are addressed.


Tidying rooms and tending hearts: An explorative, mixed-methods study of hospital cleaning staff's experiences with seriously ill and dying patients.
Palliative care is based on multi-professional team work. In this study, we investigated how cleaning staff communicate and interact with seriously ill and dying patients as well as how cleaning staff cope with the situation of death and dying. Sequential mixed methods, consisting of semi-structured interviews, focus groups, and a questionnaire. Interviews and focus group discussions were content analyzed and results were used to create a questionnaire. Quantitative data were submitted to descriptive analysis. Large university clinic in southern Germany. A total of 10 cleaning staff participated in the interviews and 6 cleaning staff took part in the focus group discussion. In addition, three managerial cleaning staff participated in a separate focus group. Questionnaires were given to all cleaning staff ( n = 240) working at the clinic in September 2008, and response rate was 52% (125/240). Cleaning staff described interactions with patients as an important and fulfilling aspect of their work. About half of participants indicated that patients talk with them every day, on average for 1-3 min. Conversations often revolved around casual topics such as weather and family, but patients also discussed their illness and, occasionally, thoughts regarding death with cleaning staff. When patients addressed illness and death, cleaning staff often felt uncomfortable and helpless. Cleaning staff perceive that they have an important role in the clinic-not only cleaning but also supporting patients. Likewise, patients appreciate being able to speak openly with cleaning staff. Still, it appears that cleaning staff may benefit from additional training in communication about sensitive issues such as illness and death.


Evidence for functional diversification within a fungal NEP1-like protein family.
In this study, we functionally analyzed the gene family encoding necrosis- and ethylene-inducing-like proteins (NLP) of the vascular wilt pathogen Verticillium dahliae. We show that the composition of the NLP gene family varies little among V. dahliae isolates. The cytotoxic activity of NLP family members of a tomato-pathogenic V. dahliae strain was determined, demonstrating that only two of the seven NLP induced plant cell death. The genes encoding these cytotoxic NLP were found to be induced in V. dahliae upon colonization of tomato. Interestingly, targeted deletion of either of the two genes in V. dahliae significantly compromised virulence on tomato as well as on Arabidopsis plants, whereas deletion of only one of the two genes affected virulence on Nicotiana benthamiana. This could be attributed to differential induction of the two NLP genes in V. dahliae upon N. benthamiana colonization, revealing that the in planta induction of NLP genes varies between plant hosts. Intriguingly, one of the NLP genes appears to also affect vegetative growth and conidiospore production, because the corresponding deletion strain produced significantly fewer conidiospores and developed extensive aerial mycelium. In conclusion, we demonstrate that the expanded V. dahliae NLP family shows functional diversification, revealing not only differential cytotoxicity between family members but also that the cytotoxic NLP play a role in vegetative growth and asexual reproduction in addition to their contribution to virulence.


Intra Nasal In situ Gelling System of Lamotrigine Using Ion Activated Mucoadhesive Polymer.
A novel drug delivery system for treating acute epileptic condition. To develop an intranasal mucoadhesive formulation of Lamotrigine (LTG) loaded insitu gel, for the treatment of epilepsy to avoid possible side effects and first pass metabolism associated with conventional treatment. Lamotrigine was loaded into different polymeric solutions of gellan and xanthan gum. All formulations subjected to various evaluation studies were within their acceptable limits. The pH of formulation ranges between 5.8 ±.001 to 6.8 ±.005 indicating that no mucosal irritation is expected as pH was in acceptable range. Invitro drug release from the mucoadhesive insitu gel formulations showed immediate drug release pattern with a maximum drug release of 97.02 ±0.54% for optimized G5 formulation within 20min. Exvivo permeation studies of optimized formulation G5 and control formulation was estimated. Exvivo permeation studies of G5 insitu formulation done for a period of 12 h resulted in slow, sustained release and greater permeability significance(P <0.05) through nasal mucosa when compared to control. Histopathological studies showed that G5 formulation was safer for nasal administration without any irritation. The stability studies indicated that gels were stable over 45 days in refrigerated condition (4±2ºC). The intranasal insitu gelling system is a promising novel drug delivery system for an antiepileptic drug lamotrigine which could enhance nasal residence time with increased viscosity and mucoadhesive character and provided better release profile of drug for treating acute epileptic conditions.


TLR9 and TLR7/8 activation induces formation of keratic precipitates and giant macrophages in the mouse cornea.
Macrophage adherence to the inner corneal surface and formation of MGCs in the stroma are common signs of chronic inflammation following corneal infection. To determine whether macrophage adherence (known clinically as KPs) and giant cell formation were specific to innate immune activation via particular TLR ligands, macrophage activation was examined in a murine model of TLR-mediated corneal inflammation. The corneal epithelium was debrided and highly purified TLR ligands were topically applied once to the cornea of TLR7(-/-), TLR9(-/-), Cx3cr1(gfp/+), CD11c(eYFP), and IL-4(-/-) mice. At 1 week post-treatment macrophage activation and phenotype was evaluated in the cornea. Treatment with TLR2, TLR3, TLR4, and TLR5 ligands caused an increase in the number of activated stromal macrophages in the central cornea at 1 week post-treatment. However, treatment with TLR9 ligand CpG-ODN and the TLR7/8 ligand R848/Resiquimod led to an accumulation of macrophages on the corneal endothelium and formation of multinucleated giant macrophages in the corneal stroma. We suggest that giant cell formation, which is a characteristic feature of granuloma formation in many tissues, may be a unique feature of TLR9- and TLR7/8-mediated macrophage activation.


Radial Tunnel Syndrome.
Radial tunnel syndrome is defined as a compressive neuropathy of the posterior interosseus nerve. It is differentiated from posterior interosseus nerve compression by symptom profile. The purpose of this article is to review past and current literature on the topic and determine if there are any emerging treatment options for this condition. Traditionally, conservative management of Radial Tunnel syndrome has been relatively unsuccessful. As a result, patients afflicted by this neuropathy require operative intervention. Effectiveness of surgical decompression is variable and can range from 67 to 92% but currently remains the standard treatment. However, there are some conservative treatment options that have been recently reported that show promising results. Such treatments include dry needling of the affected area and ultrasound guided corticosteroid injections to hydro dissect around the posterior interosseus nerve at sites of compression. Radial tunnel syndrome is an uncommon and unique peripheral neuropathy. It involves the posterior interosseus nerve however it can be differentiated from PIN syndrome based on the symptom profile. There are various compressive etiologies that can cause a patient to become symptomatic; therefore it is important to critically assess the patient and their symptoms and use appropriate imaging to determine the cause and appropriate treatment. Typically, conservative treatments are attempted first. Traditionally, conservative therapy is unsuccessful and operative decompression is necessary. However, current literature highlights various new nonsurgical options that suggest some promise and could be alternatives to surgical decompression.


Mental illness and changing definitions of disability under the Americans With Disabilities Act.
The Americans With Disabilities Act (ADA) prohibits employment discrimination on the basis of disability. Originally, an assessment of whether a person had a disability and thus was protected by the ADA examined the person's impairment in its uncorrected state. Thus it was comparatively easy for people with mental illness to meet the threshold requirement for having a disability. However, in 1999 the U.S. Supreme Court issued three decisions holding that, for the purposes of the ADA, disability had to be assessed in its corrected state. Since those decisions were issued, the courts have increased the burden on individuals, including people with mental illness, to prove that they have a disability. In several cases, courts ruled that people with serious mental illnesses do not have a disability and are not protected by the ADA. This article discusses these cases and their implications for people with mental illness and for practitioners.


Canadian pediatric emergency physician knowledge of concussion diagnosis and initial management.
Introduction The diagnosis of concussion is a critical step in the appropriate management of patients following minor head trauma. The authors hypothesized that wide practice variation exists among pediatric emergency medicine physicians in the application of physical and cognitive rest recommendations following an acute concussion. The authors developed a 35-item questionnaire incorporating case vignettes to examine pediatric emergency physician knowledge of concussion diagnosis, understanding of initial management using return-to-play/school/work guidelines, use of existing concussion protocols, and perceived barriers to protocol use. Using a modified Dillman technique, the authors distributed an online survey to members of Pediatric Emergency Research Canada, a national association of pediatric emergency physicians. Of 176 potential participants, 115 (65%) responded to the questionnaire, 89% (95% confidence interval [CI]: 0.81, 0.93) of whom reported having diagnosed 20 or more concussions annually. Although 90% (95% CI: 0.83, 0.94) of respondents adequately diagnosed concussion, only 64% (95% CI: 0.54, 0.72) correctly applied graduated return-to-play guidelines. Cognitive rest recommendations were also frequently limited: 40% (95% CI: 0.31, 0.49) did not recommend school absence, 30% (95% CI: 0.22, 0.39) did not recommend schoolwork reduction, and 35% (95% CI: 0.27, 0.45) did not recommend limiting screen time. Eighty percent (95% CI: 0.72, 0.87) of respondents reported having used guidelines frequently or always to guide clinical decisions regarding concussion. Despite a proficiency in the diagnosis of concussion, pediatric emergency physicians exhibit wide variation in recommending the graduated return to play and cognitive rest following concussion.


Therapeutic Effect of Cilostazol Ophthalmic Nanodispersions on Retinal Dysfunction in Streptozotocin-Induced Diabetic Rats.
We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnano into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZnano had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZnano attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZnano Thus, we have found that a-wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZnano. These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs.


Characterization of the molecular mechanisms of silicon uptake in coccolithophores.
Coccolithophores are an important group of calcifying marine phytoplankton. Although coccolithophores are not silicified, some species exhibit a requirement for Si in the calcification process. These species also possess a novel protein (SITL) that resembles the SIT family of Si transporters found in diatoms. However, the nature of Si transport in coccolithophores is not yet known, making it difficult to determine the wider role of Si in coccolithophore biology. Here, we show that coccolithophore SITLs act as Na+ -coupled Si transporters when expressed in heterologous systems and exhibit similar characteristics to diatom SITs. We find that CbSITL from Coccolithus braarudii is transcriptionally regulated by Si availability and is expressed in environmental coccolithophore populations. However, the Si requirement of C. braarudii and other coccolithophores is very low, with transport rates of exogenous Si below the level of detection in sensitive assays of Si transport. As coccoliths contain only low levels of Si, we propose that Si acts to support the calcification process, rather than forming a structural component of the coccolith itself. Si is therefore acting as a micronutrient in coccolithophores and natural populations are only likely to experience Si limitation in circumstances where dissolved silicon (DSi) is depleted to extreme levels.


Time course of sleep inertia after nighttime and daytime sleep episodes.
Sleep inertia refers to the period of reduced vigilance following upon awakening from sleep. To investigate the time course of sleep inertia, self-ratings of alertness and reaction time in a memory task were repeatedly assessed after nighttime and daytime sleep episodes in healthy young men. Alertness gradually increased and reaction time gradually decreased within the first hour after awakening. Their time course could be described by exponential functions with time constants of 0.45 h and 0.3 h, respectively. The data demonstrate that sleep inertia is a robust, quantifiable process that can be incorporated in models of sleep and vigilance.


Magnetic imaging by x-ray holography using extended references.
We demonstrate magnetic lensless imaging by Fourier transform holography using extended references. A narrow slit milled through an opaque gold mask is used as a holographic reference and magnetic contrast is obtained by x-ray magnetic circular dichroism. We present images of magnetic domains in a Co/Pt multilayer thin film with perpendicular magnetic anisotropy. This technique holds advantages over standard Fourier transform holography, where small holes are used to define the reference beam. An increased intensity through the extended reference reduces the counting time to record the farfield diffraction pattern. Additionally it was found that manufacturing narrow slits is less technologically demanding than the same procedure for holes. We achieve a spatial resolution of ∼30 nm, which was found to be limited by the sample period of the chosen experimental setup.


Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus.
The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIVmac239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.


Seed metabolomic study reveals significant metabolite variations and correlations among different soybean cultivars.
Soybean [Glycine max (L.) Merr.] is one of the world's major crops, and soybean seeds are a rich and important resource for proteins and oils. While "omics" studies, such as genomics, transcriptomics, and proteomics, have been widely applied in soybean molecular research, fewer metabolomic studies have been conducted for large-scale detection of low molecular weight metabolites, especially in soybean seeds. In this study, we investigated the seed metabolomes of 29 common soybean cultivars through combined gas chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry. One hundred sixty-nine named metabolites were identified and subsequently used to construct a metabolic network of mature soybean seed. Among the 169 detected metabolites, 104 were found to be significantly variable in their levels across tested cultivars. Metabolite markers that could be used to distinguish genetically related soybean cultivars were also identified, and metabolite-metabolite correlation analysis revealed some significant associations within the same or among different metabolite groups. Findings from this work may potentially provide the basis for further studies on both soybean seed metabolism and metabolic engineering to improve soybean seed quality and yield.


Predictors for long-term outcome and quality of life of patients after cardiac surgery with prolonged intensive care unit stay.
This study investigated factors determining the long-term outcome and quality of life of patients with a prolonged intensive care unit (ICU) stay after cardiac surgery. A retrospective analysis was performed in 230 patients that had undergone cardiac surgery and suffered from a post-operative ICU stay of 7 or more days at our institution. Among 11 pre-, 13 intra-, and 14 post-operative variables, factors influencing 5-year outcome were identified by logistic regression analysis. Quality of life was determined using the Short Form-36 questionnaire. In-hospital mortality was 12%. One hundred and eleven of 187 patients (59%) were alive after 5 years. Non-survivors were older (70 vs. 65 years, p = 0.005) and had a higher additive EuroSCORE (7 vs. 5, p = 0.034). Logistic regression identified pre-operative atrial fibrillation (AF), (28 vs. 10%, p = 0.003) as the strongest predictor for a 5-year outcome, followed by myocardial infarction (62 vs. 41%, p = 0.005), and prolonged mechanical ventilation (8 vs. 5 days, p = 0.036). Survivors did not show an impaired physical component summary SF-36 score (39 vs. 46, p = 0.737) or mental component summary score (55 vs. 55, p = 0.947) compared to an age-matched German Normative Sample. Pre-operative AF proved to be the most important factor determining the 5-year outcome of patients with a prolonged ICU stay after cardiac surgery. Neither physical nor mental health appeared to be impaired in these patients.


New Crystallographic Snapshots of Large Domain Movements in Bacterial 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase.
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) catalyzes the first committed step of the mevalonate pathway, which is used across biology in the biosynthesis of countless metabolites. HMGR consumes 2 equiv of the cofactor NAD(P)H to perform the four-electron reduction of HMG-CoA to mevalonate toward the production of steroids and isoprenoids, the largest class of natural products. Recent structural data have shown that HMGR contains a highly mobile C-terminal domain (CTD) that is believed to adopt many different conformations to permit binding and dissociation of the substrate, cofactors, and products at specific points during the reaction cycle. Here, we have characterized the HMGR from Delftia acidovorans as an NADH-specific enzyme and determined crystal structures of the enzyme in unbound, mevalonate-bound, and NADH- and citrate-bound states. Together, these structures depict ligand binding in both the active site and the cofactor-binding site while illustrating how a conserved helical motif confers NAD(P)H cofactor specificity. Unexpectedly, the NADH-bound structure also reveals a new conformation of the CTD, in which the domain has "flipped" upside-down, while directly binding the cofactor. By capturing these structural snapshots, this work not only expands the known range of HMGR domain movement but also provides valuable insight into the catalytic mechanism of this biologically important enzyme.


Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results.
Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, double-blind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatment with at least partial benefit were crossed over to fluoxetine treatment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symptoms that were comparable with precrossover ratings completed during clomipramine treatment. A significant exacerbation in obsessive-compulsive disorder and depression ratings as well as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder. Platelet 5-HT concentrations were reduced 95% during both clomipramine and fluoxetine treatment periods. These results suggest that fluoxetine may represent a viable alternative to clomipramine in the treatment of obsessive-compulsive disorder, although further studies with larger sample sizes are needed.


Resistance to reinfection in chinook salmon Oncorhynchus tshawytscha to Loma salmonae (Microsporidia).
Chinook salmon Oncorhynchus tshawytscha were experimentally infected per os with Loma salmonae and held in flow-through seawater tanks at 12 to 14 degrees C. The fish exhibited 100% infection when first examined at 7 wk post initial exposure (p.e.), and by 20 wk p.e. they had completely recovered from gill infections. The recovered fish were then re-exposed the following week. All of these fish showed strong protection to new L. salmonae infections, while naïve fish exposed to the same inoculum developed the infection. Most of the re-exposed fish exhibited a few free spores or spores within phagocytes in the kidney interstitium at 20 to 29 wk p.e., but xenomas were not detected in either the gills or visceral organs. The kidney is the primary site of reticulo-endothelial activity, and thus these spores were likely deposited in the kidney by entrapment by fixed macrophages. It is possible that these spores provide immunologic stimuli to reinforce the resistance to new L. salmonae infections.


Network-centric Analysis of Genetic Predisposition in Diabetic Nephropathy.
Diabetic nephropathy is a serious, long-term complication of diabetes and the leading cause of end-stage renal disease throughout the world. Although this disease is progressively imposing a heavier burden on the health care system, in many aspects it remains poorly understood. In addition to environmental influences, there is abundant evidence in support of genetic susceptibility to microvascular complications of nephropathy in diabetic patients. Familial clustering of phenotypes such as end-stage renal disease, albuminuria and kidney disease have been reported in large scale population studies throughout the world demonstrating strong contribution of inherited factors. Recent genome-wide linkage scans identified several chromosomal regions that are likely to contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under linkage peaks. In this review we have extracted from the literature the most promising candidate genes thought to confer susceptibility to diabetic nephropathy and mapped them to affected pathways by using network-centric analysis. Several of the top susceptibility genes have been identified as network hubs and bottlenecks suggesting that they might be important agents in the onset of diabetic nephropathy.


Making use of apex predator sample collections: an integrated workflow for quality assured sample processing, analysis and digital sample freezing of archived samples.
Using monitoring data from apex predators for chemicals risk assessment can provide important information on bioaccumulating as well as biomagnifying chemicals in food webs. A survey among European institutions involved in chemical risk assessment on their experiences with apex predator data in chemical risk assessment revealed great interest in using such data. However, the respondents indicated that constraints were related to expected high costs, lack of standardisation and harmonised quality criteria for exposure assessment, data access, and regulatory acceptance/application. During the Life APEX project, we demonstrated that European sample collections (i.e. environmental specimen banks (ESBs), research collection (RCs), natural history museums (NHMs)) archive a large variety of biological samples that can be readily used for chemical analysis once appropriate quality assurance/control (QA/QC) measures have been developed and implemented. We therefore issued a second survey on sampling, processing and archiving procedures in European sample collections to derive key quality QA/QC criteria for chemical analysis. The survey revealed great differences in QA/QC measures between ESBs, NHMs and RCs. Whereas basic information such as sampling location, date and biometric data were mostly available across institutions, protocols to accompany the sampling strategy with respect to chemical analysis were only available for ESBs. For RCs, the applied QA/QC measures vary with the respective research question, whereas NHMs are generally less aware of e.g. chemical cross-contamination issues. Based on the survey we derived key indicators for assessing the quality of biota samples that can be easily implemented in online databases. Furthermore, we provide a QA/QC workflow not only for sampling and processing but also for the chemical analysis of biota samples. We focussed on comprehensive analytical techniques such as non-target screening and provided insights into subsequent storage of high-resolution chromatograms in online databases (i.e. digital sample freezing platform) to ultimately support chemicals risk assessment.


Long-term effects of 900 MHz radiofrequency radiation emitted from mobile phone on testicular tissue and epididymal semen quality.
The purpose of this study is to bridge this gap by investigating effects of long term 900 MHz mobile phone exposure on reproductive organs of male rats. The study was carried out on 14 adult Wistar Albino rats by dividing them randomly into two groups (n: 7) as sham group and exposure group. Rats were exposed to 900 MHz radiofrequency (RF) radiation emitted from a GSM signal generator. Point, 1 g and 10 g specific absorption rate (SAR) levels of testis and prostate were found as 0.0623 W/kg, 0.0445 W/kg and 0.0373 W/kg, respectively. The rats in the exposure group were subject to RF radiation 3 h per day (7 d a week) for one year. For the sham group, the same procedure was applied, except the generator was turned off. At the end of the study, epididymal sperm concentration, progressive sperm motility, abnormal sperm rate, all-genital organs weights and testis histopathology were evaluated. Any differences were not observed in sperm motility and concentration (p > 0.05). However, the morphologically normal spermatozoa rates were found higher in the exposure group (p < 0.05). Although histological examination showed similarity in the seminiferous tubules diameters in both groups, tunica albuginea thickness and the Johnsen testicular biopsy score were found lower in the exposure group (p < 0.05, p < 0.0001). In conclusion, we claim that long-term exposure of 900 MHz RF radiation alter some reproductive parameters. However, more supporting evidence and research is definitely needed on this topic.


Functional Metagenomics of Spacecraft Assembly Cleanrooms: Presence of Virulence Factors Associated with Human Pathogens.
Strict planetary protection practices are implemented during spacecraft assembly to prevent inadvertent transfer of earth microorganisms to other planetary bodies. Therefore, spacecraft are assembled in cleanrooms, which undergo strict cleaning and decontamination procedures to reduce total microbial bioburden. We wanted to evaluate if these practices selectively favor survival and growth of hardy microorganisms, such as pathogens. Three geographically distinct cleanrooms were sampled during the assembly of three NASA spacecraft: The Lockheed Martin Aeronautics' Multiple Testing Facility during DAWN, the Kennedy Space Center's Payload Hazardous Servicing Facility (KSC-PHSF) during Phoenix, and the Jet Propulsion Laboratory's Spacecraft Assembly Facility during Mars Science Laboratory. Sample sets were collected from the KSC-PHSF cleanroom at three time points: before arrival of the Phoenix spacecraft, during the assembly and testing of the Phoenix spacecraft, and after removal of the spacecraft from the KSC-PHSF facility. All samples were subjected to metagenomic shotgun sequencing on an Illumina HiSeq 2500 platform. Strict decontamination procedures had a greater impact on microbial communities than sampling location Samples collected during spacecraft assembly were dominated by Acinetobacter spp. We found pathogens and potential virulence factors, which determine pathogenicity in all the samples tested during this study. Though the relative abundance of pathogens was lowest during the Phoenix assembly, potential virulence factors were higher during assembly compared to before and after assembly, indicating a survival advantage. Decreased phylogenetic and pathogenic diversity indicates that decontamination and preventative measures were effective against the majority of microorganisms and well implemented, however, pathogen abundance still increased over time. Four potential pathogens, Acinetobacter baumannii, Acinetobacter lwoffii, Escherichia coli and Legionella pneumophila, and their corresponding virulence factors were present in all cleanroom samples. This is the first functional metagenomics study describing presence of pathogens and their corresponding virulence factors in cleanroom environments. The results of this study should be considered for microbial monitoring of enclosed environments such as schools, homes, hospitals and more isolated habitation such the International Space Station and future manned missions to Mars.


Complete Genome Sequence of Bacillus megaterium Strain TG1-E1, a Plant Drought Tolerance-Enhancing Bacterium.
Based on a combination of next-generation sequencing and single-molecule sequencing, we obtained the whole-genome sequence of Bacillus megaterium strain TG1-E1, which is a highly salt-tolerant rhizobacterium that enhances plant tolerance to drought stress. The complete genome is estimated to be approximately 5.48 Mb containing a total of 5,858 predicted protein-coding DNA sequences.


Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma.
Noneosinophilic asthma is common across asthma severities. However, in patients with moderate-to-severe disease, the absence of sputum eosinophilia cannot distinguish between asthmatic subjects with eosinophilic inflammation controlled by corticosteroids versus those in whom eosinophilic inflammation is not a component of the disease. We sought to develop a method to quantify eosinophil proteins in airway macrophages as a novel biomarker of eosinophilic airway inflammation. Eosinophil proteins in airway macrophages were assessed by means of flow cytometry, immunofluorescence, and cytoplasmic hue change after ingestion of apoptotic eosinophils. Airway macrophage median percentage of red-hued area in stained sputum cytospin preparations was assessed by means of image analysis from (1) subjects with mild-to-severe asthma, subjects with nonasthmatic eosinophilic bronchitis, and healthy control subjects; (2) subjects with eosinophilic severe asthma after treatment with prednisolone; and (3) subject with noneosinophilic asthma before corticosteroid withdrawal. Eosinophil proteins were detected in airway macrophages, and cytoplasmic red hue increased after ingestion of apoptotic eosinophils. Airway macrophage percentage redhued area was increased in subjects with moderate-to-severe asthma compared with that seen in subjects with mild asthma and healthy control subjects, was similar in those with or without a sputum eosinophilia, and was increased after corticosteroid therapy. In asthmatic subjects without sputum eosinophilia, the airway macrophage percentage red-hued area was increased in subjects who did versus those who did not have sputum eosinophilia after corticosteroid withdrawal. Eosinophil proteins can be reliably measured in airway macrophages. In combination with sputum eosinophilia, the macrophage eosinophil protein content might further define the asthma phenotype and provide an additional tool to direct therapy.


The SHED-IT weight loss maintenance trial protocol: A randomised controlled trial of a weight loss maintenance program for overweight and obese men.
Despite short-term efficacy, many weight loss studies demonstrate poor long-term results and have difficulty recruiting men. Cost-effective treatments that help men achieve long-term weight loss are required. Using a two-phase, assessor-blinded, parallel-group randomised controlled trial design this study will test the effectiveness and cost-effectiveness of a male-only weight loss maintenance intervention. In Phase I (3 months) 209 men received the SHED-IT Weight Loss Program. In Phase II (12 months) 92 men who lost 4 kg or more were randomised to either (i) a maintenance group who received the 6-month, gender-tailored SHED-IT Weight Loss Maintenance Program, which included no face-to-face contact (n = 47), or (ii) a self-help control group (n = 45). Randomisation was stratified by weight loss (4 kg-7.4 kg, ≥7.5 kg) and BMI (<30 kg/m(2), ≥30 kg/m(2)). Assessments occurred at 'study entry' (start of Phase I), 'baseline' (start of Phase II), '6 months' (post-test) and will occur at '12 months' (follow-up; primary endpoint). The primary outcome is weight change in Phase II (i.e. from 'baseline' at 12 months after randomization). Secondary outcomes include waist circumference (umbilicus and narrowest), blood pressure, body composition, objectively measured physical activity, sedentary time, portion size, dietary intake, quality of life, depressive symptoms, and behavioural cognitions. Costing data will be collected for cost-effectiveness analysis. Generalised linear mixed models (intention-to-treat) will assess outcomes for treatment (maintenance vs. control), time (baseline, 6-month and 12-month) and the treatment-by-time interaction. This will be the first study to evaluate a male-only, gender-targeted weight loss maintenance program. Results will provide evidence regarding feasible and theoretically-driven obesity treatments for men with potential for long-term impact and widespread dissemination. Australian New Zealand Clinical Trials Registry (ACTRN12612000749808).


Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery.
Growth-differentiation factor-15 (GDF-15) is an emerging humoral marker for risk stratification in cardiovascular disease. Cardiac-surgery-associated acute kidney injury (CSA-AKI), an important complication in patients undergoing cardiac surgery, is associated with poor prognosis. The present secondary analysis of an observational cohort study aimed to determine the role of GDF-15 in predicting CSA-AKI compared with the Cleveland-Clinic Acute Renal Failure (CC-ARF) score and a logistic regression model including variables associated with renal dysfunction. Preoperative plasma GDF-15 was determined in 1176 consecutive patients undergoing elective cardiac surgery. Patients with chronic kidney disease stage 5 were excluded. AKI was defined according to Kidney-Disease-Improving-Global-Outcomes (KDIGO) - creatinine criteria. The following variables were screened for association with development of postoperative AKI: age, gender, additive Euroscore, serum creatinine, duration of cardiopulmonary bypass, duration of surgery, type of surgery, total circulatory arrest, preoperative hemoglobin, preoperative oxygen-supplemented cerebral oxygen saturation, diabetes mellitus, hemofiltration during ECC, plasma GDF-15, high sensitivity troponin T (hsTNT), and N-terminal prohormone of B-type natriuretic peptide (NTproBNP). There were 258 patients (21.9 %) with AKI (AKI stage 1 (AKI-1), n = 175 (14.9 %); AKI-2, n = 6 (0.5 %); AKI-3, n = 77 (6.5 %)). The incidence of AKI-1 and AKI-3 increased significantly from the lowest to the highest tertiles of GDF-15. In logistic regression, preoperative GDF-15, additive Euroscore, age, plasma creatinine, diabetes mellitus, and duration of cardiopulmonary bypass were independently associated with AKI. Inclusion of GDF-15 in a logistic regression model comprising these variables significantly increased the area under the curve (AUC 0.738 without and 0.750 with GDF-15 included) and the net reclassification ability to predict AKI. Comparably, in receiver operating characteristic analysis the predictive capacity of the CC-ARF score (AUC 0.628) was improved by adding GDF-15 (AUC 0.684) but this score also had lower predictability than the logistic regression model. In random forest analyses the predictive capacity of GDF-15 was especially pronounced in patients with normal plasma creatinine. This suggests that preoperative plasma GDF-15 independently predicts postoperative AKI in patients undergoing elective cardiac surgery and is particularly helpful for risk stratification in patients with normal creatinine. NCT01166360 on July 20, 2010.


Excitation-contraction coupling and extracellular calcium transients in rabbit atrium: reconstruction of basic cellular mechanisms.
Interactions of electrogenic sodium-calcium exchange, calcium channel and sarcoplasmic reticulum in the mammalian heart have been explored by simulation of extracellular calcium transients measured with tetramethylmurexide in rabbit atrium. The approach has been to use the simplest possible formulations of these mechanisms, which together with a minimum number of additional mechanisms allow reconstruction of action potentials, intracellular calcium transients and extracellular calcium transients. A 3:1 sodium-calcium exchange stoichiometry is assumed. Calcium-channel inactivation is assumed to take place by a voltage-dependent mechanism, which is accelerated by a rise in intracellular calcium; intracellular calcium release becomes a major physiological regulator of calcium influx via calcium channels. A calcium release mechanism is assumed, which is both calcium- and voltage-sensitive, and which undergoes prolonged inactivation. 200 microM cytosolic calcium buffer is assumed. For most simulations only instantaneous potassium conductances are simulated so as to study the other mechanisms independently of time- and calcium-dependent outward current. Thus, the model reconstructs extracellular calcium transients and typical action-potential configuration changes during steady-state and non-steady-state stimulation from the mechanisms directly involved in trans-sarcolemmal calcium movements. The model predicts relatively small trans-sarcolemmal calcium movements during regular stimulation (ca. 2 mumol kg-1 fresh mass per excitation); calcium current is fully activated within 2 ms of excitation, inactivation is substantially complete within 30 ms, and sodium-calcium exchange significantly resists repolarization from approximately -30 mV. Net calcium movements many times larger are possible during non-steady-state stimulation. Long action potentials at premature excitations or after inhibition of calcium release can be supported almost exclusively by calcium current (net calcium influx 5-30 mumol kg-1 fresh mass); action potentials during potentiated post-stimulatory contractions can be supported almost exclusively by sodium-calcium exchange (net calcium efflux 4-20 mumol kg-1 fresh mass). Large calcium movements between the extracellular space and the sarcoplasmic reticulum can take place through the cytosol with virtually no contractile activation. The simulations provide integrated explanations of electrical activity, contractile function and trans-sarcolemmal calcium movements, which were outside the explanatory range of previous models.


A comparison of reproductive parameters of female Amur tigers (Panthera tigris altaica) in the wild and captivity.
A healthy population of captive Amur tigers might assist recovery of the wild population in Northeast China if individuals were properly prepared and considered suitable for release in the wild. We analyzed the breeding records of 68 female Amur tigers from 1995 to 2010 in the Hengdaohezi Felid Breeding Center of China and compared the reproductive parameters of this population to wild female Amur tigers. We found that the reproductive parameters of the captive population (the age of first parturition, length of gestation and litter survival rate) were not significantly different from those of wild Amur tigers. Differences in birth date and litter size between wild and captive populations may be caused by management protocols for the captive population or insufficient field data from the wild population. Reproductive parameters of females giving birth after losing a litter were similar to parameters of females that did not lose a litter, except for birth date. These results provide no indication of major problems in using captive females for a breeding program for release of cubs into the wild, but additional information is still needed to assess their suitability.


Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure.
Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal-associated membrane protein type 2 (LAMP-2). Emerging evidence has highlighted the importance of autophagy in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. To investigate the molecular mechanisms responsible for Danon disease, we created induced pluripotent stem cells (iPSCs) from two patients with different LAMP-2 mutations. Danon iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired autophagic flux and key features of heart failure such as increased cell size, increased expression of natriuretic peptides, and abnormal calcium handling compared to control iPSC-CMs. Additionally, Danon iPSC-CMs demonstrated excessive amounts of mitochondrial oxidative stress and apoptosis. Using the sulfhydryl antioxidant N-acetylcysteine to scavenge free radicals resulted in a significant reduction in apoptotic cell death in Danon iPSC-CMs. In summary, we have modeled Danon disease using human iPSC-CMs from patients with mutations in LAMP-2, allowing us to gain mechanistic insight into the pathogenesis of this disease. We demonstrate that LAMP-2 deficiency leads to an impairment in autophagic flux, which results in excessive oxidative stress, and subsequent cardiomyocyte apoptosis. Scavenging excessive free radicals with antioxidants may be beneficial for patients with Danon disease. In vivo studies will be necessary to validate this new treatment strategy.


What Goes Around Comes Around … Or Does It? Disrupting the Cycle of Traditional, Sport-Based Physical Education.
As typically taught, sport-based, multiactivity approaches to physical education provide students with few opportunities to increase their skill, fitness, or understanding. Alternative curriculum models, such as Sport Education, Teaching Games for Understanding, and Fitness for Life, represent a second generation of models that build on strong statements of democratic, student-centered practice in physical education. In the What Goes Around section of the paper, I discuss the U.S. perspective on the origins of alternative physical education curriculum models introduced in the early and mid-20th century as a response to sport and exercise programs of the times. Today, with the help of physical educators, scholars are conducting research to test new curricular alternatives or prototypes to provide evidence-based support for these models. Yet, the multiactivity, sport-based curriculum continues to dominate in most U.S. physical education classes. I discuss reasons for this dogged persistence and propose reforms to disrupt this pervasive pattern in the future.


Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.
Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.


Rapid Molecular Detection of Zika Virus in Acute-Phase Urine Samples Using the Recombinase Polymerase Amplification Assay.
Currently the detection of Zika virus (ZIKV) in patient samples is done by real-time RT-PCR. Samples collected from rural area are sent to highly equipped laboratories for screening. A rapid point-of-care test is needed to detect the virus, especially at low resource settings. In this report, we describe the development of a reverse transcription isothermal recombinase polymerase amplification (RT-RPA) assay for the identification of ZIKV. RT-RPA assay was portable, sensitive (21 RNA molecules), and rapid (3-15 minutes). No cross-reactivity was detected to other flaviviruses, alphaviruses and arboviruses. Compared to real-time RT-PCR, the diagnostic sensitivity was 92%, while the specificity was 100%. The developed assay is a promising platform for rapid point of need detection of ZIKV in low resource settings and elsewhere (e.g. during mass gathering).


Renal disease disparities in Asian and Pacific-based populations in Hawai'i.
The prevalence of end-stage renal disease (ESRD) in the United States is expected to double over the next 10 years. The identification of ethnic differences in the prevalence, treatment, morbidity, and mortality related to chronic kidney disease (CKD) is of great concern. Asian Americans comprise a rapidly expanding sector of the U.S. population and are reported to have ESRD growth rates that are approximately 50% higher than caucasians. Hawai'i has a large, well-established Asian and Pacific-based population that facilitates the examination of disparities in renal disease among the state's diverse ethnic groups. The prevalence of ESRD in Hawai'i has continued to rise due, in part, to high rates of diabetes, glomerulonephritis, and hypertension reported in Asian Americans and Pacific-based populations. ESRD patients in Hawai'i have a two-fold higher prevalence of glomerulonephritis, compared with the general ESRD population in the United States. Other potential sources of renal disparities-such as cultural factors, language barriers, and health access factors-among Hawaii's major ethnic groups are assessed. However, few studies have examined the relative contribution of these potential factors. Consequently, efforts to reduce and eventually eliminate renal disease disparities will require a better understanding of the major sources of health disparities, such as timely medical care, a diverse health workforce, and cultural/social barriers, that affect optimal health care practices in Asian and Pacific-based populations.


Panhistone deacetylase inhibitors inhibit proinflammatory signaling pathways to ameliorate interleukin-18-induced cardiac hypertrophy.
We investigated the genome-wide consequences of pan-histone deacetylase inhibitors (HDACIs) trichostatin A (TSA) and m-carboxycinnamic acid bis-hydroxamide (CBHA) in the hearts of BALB/c mice eliciting hypertrophy in response to interleukin-18 (IL-18). Both TSA and CBHA profoundly altered cardiac chromatin structure that occurred concomitantly with normalization of IL-18-induced gene expression and amelioration of cardiac hypertrophy. The hearts of mice exposed to IL-18+/-TSA or CBHA elicited distinct gene expression profiles. Of 184 genes that were differentially regulated by IL-18 and TSA, 33 were regulated in an opposite manner. The hearts of mice treated with IL-18 and/or CBHA elicited 147 differentially expressed genes (DEGs), a third of which were oppositely regulated by IL-18 and CBHA. Ingenuity Pathways and Kyoto Encyclopedia of Genes and Genomes analyses of DEGs showed that IL-18 impinged on TNF-α- and IFNγ-specific gene networks relegated to controlling immunity and inflammation, cardiac metabolism and energetics, and cell proliferation and apoptosis. These TNF-α- and IFNγ-specific gene networks, extensively connected with PI3K, MAPK, and NF-κB signaling pathways, were oppositely regulated by IL-18 and pan-HDACIs. Evidently, both TSA and CBHA caused a two- to fourfold induction of phosphatase and tensin homolog expression to counteract IL-18-induced proinflammatory signaling and cardiac hypertrophy.


Lanthanide-induced relaxation anisotropy.
Lanthanide ions accelerate nuclear spin relaxation by two primary mechanisms: dipolar and Curie. Both are commonly assumed to depend on the length of the lanthanide-nucleus vector, but not on its direction. Here we show experimentally that this is wrong - careful proton relaxation data analysis in a series of isostructural lanthanide complexes (Ln = Tb, Dy, Ho, Er, Tm, Yb) reveals angular dependence in both Curie and dipolar relaxation. The reasons are: (a) that magnetic susceptibility anisotropy can be of the same order of magnitude as the isotropic part (contradicting the unstated assumption in Guéron's theory of the Curie relaxation process), and (b) that zero-field splitting can be much stronger than the electron Zeeman interaction (Bloembergen's original theory of the lanthanide-induced dipolar relaxation process makes the opposite assumption). These factors go beyond the well researched cross-correlation effects; they alter the relaxation theory treatment and make strong angular dependencies appear in the nuclear spin relaxation rates. Those dependencies are impossible to ignore - this is now demonstrated both theoretically and experimentally, and suggests that a major revision is needed of the way lanthanide-induced relaxation data are used in structural biology.